American Journal of Respiratory and Critical Care Medicine

Rationale: Several studies in mild chronic obstructive pulmonary disease (COPD) have shown a higher than normal ventilatory equivalent for carbon dioxide (V.e/V.co2) during exercise. Our objective was to examine pulmonary gas exchange abnormalities and the mechanisms of high V.e/V.co2 in mild COPD and its impact on dyspnea and exercise intolerance.

Methods: Twenty-two subjects (11 patients with GOLD [Global Initiative for Chronic Obstructive Lung Disease] grade 1B COPD, 11 age-matched healthy control subjects) undertook physiological testing and a symptom-limited incremental cycle exercise test with arterial blood gas collection.

Measurements and Main Results: Patients (post-bronchodilator FEV1: 94 ± 10% predicted; mean ± SD) had evidence of peripheral airway dysfunction and reduced peak oxygen uptake compared with control subjects (80 ± 18 vs. 113 ± 24% predicted; P < 0.05). Arterial blood gases were within the normal range and effective alveolar ventilation was not significantly different from control subjects throughout exercise. The alveolar–arterial O2 tension gradient was elevated at rest and throughout exercise in COPD (P < 0.05). V.e/V.co2, dead space to tidal volume ratio (Vd/Vt), and arterial to end-tidal CO2 difference were all higher (P < 0.05) in patients with COPD than in control subjects during exercise. In patients with COPD versus control subjects, there was significant dynamic hyperinflation and greater tidal volume constraints (P < 0.05). Standardized dyspnea intensity ratings were also higher (P < 0.05) in patients with COPD versus control subjects in association with higher ventilatory requirements. Within all subjects, Vd/Vt correlated with the V.e/V.co2 ratio during submaximal exercise (r = 0.780, P < 0.001).

Conclusions: High Vd/Vt was the most consistent gas exchange abnormality in smokers with only mild spirometric abnormalities. Compensatory increases in minute ventilation during exercise maintained alveolar ventilation and arterial blood gas homeostasis but at the expense of earlier dynamic mechanical constraints, greater dyspnea, and exercise intolerance in mild COPD.

Scientific Knowledge on the Subject

Heterogeneous mechanical and pulmonary gas exchange impairment can exist in smokers with only minor spirometric abnormalities, but their precise clinical relevance remains unknown. The presence of a high ventilatory equivalent for CO2, suggesting reduced ventilatory efficiency, has consistently been reported in several exercise studies in mild chronic obstructive pulmonary disease, but the underlying mechanisms and consequences for exercise tolerance are poorly understood.

What This Study Adds to the Field

Increased physiological dead space and wasted ventilation were the most consistent pulmonary gas exchange abnormalities during exercise in the patients with mild chronic obstructive pulmonary disease. Although effective alveolar ventilation and arterial blood gas homeostasis were adequately preserved by compensatory increases in minute ventilation, this forced earlier dynamic respiratory mechanical constraints, greater dyspnea, and exercise intolerance in these patients despite a largely preserved FEV1.

Chronic obstructive pulmonary disease (COPD) is increasing in prevalence worldwide, and the vast majority of patients have mild airway obstruction by spirometric criteria (15). Such patients have increased all-cause mortality and reduced health-related quality of life, exercise capacity, and habitual physical activity (610). Moreover, a subset (29–44%) of these patients reports persistent and troublesome activity-related dyspnea (3, 11). Several studies have attested to the heterogeneous pathophysiological abnormalities that can exist in smokers with largely preserved spirometry (1215). Most of the more recent studies have focused on the potential role of peripheral airway dysfunction and abnormalities of dynamic respiratory mechanics in dyspnea causation and exercise intolerance in mild COPD (1418). The current study extends the previous work by primarily examining the abnormalities of pulmonary gas exchange that drive the increased total (minute) ventilation during exercise (1419).

A seminal study by Barbera and colleagues showed that in patients with mild-to-moderate COPD, the alveolar–arterial oxygen tension gradient (a–aPo2) was increased at rest and during exercise (20). The investigators further demonstrated that arterial oxygenation improved at a standardized submaximal exercise work rate as a result of increased and improved distribution of ventilation. In that study, comparison with a healthy control group was not undertaken to account for the established effects of aging on pulmonary gas exchange. Moreover, the potential role of increased wasted ventilation and its interaction with dynamic respiratory mechanics and dyspnea were not formally examined (20). More recently, Rodríguez-Roisin and colleagues confirmed widened a–aPo2 during resting breathing and predominance of lung units with low ventilation–perfusion (V.a/Q.) ratios in the majority of a subsample (n = 15) of patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 mild COPD (21).

Given the evidence of increased lung compliance, early airway closure, extensive peripheral airway dysfunction, and maldistribution of ventilation in smokers with nearly preserved spirometry (17, 22, 23), it is not surprising that an increased proportion of lung units with low V.a/Q. ratios is thought to be the dominant gas exchange abnormality in mild COPD (21). However, several exercise studies in mild COPD point to consistent abnormalities of surrogate measures of ventilatory efficiency derived from analysis of V.eV.co2 relationships (1519). Thus, the V.eV.co2 slope and nadir of the ventilatory equivalent for carbon dioxide (V.e/V.co2) during submaximal exercise were consistently higher than in age-matched healthy control subjects (1519). This is compatible with an increased dead space to tidal volume ratio (Vd/Vt), alterations in the set point for PaCO2, or both (24).

The clinical importance of ventilatory inefficiency during exercise is increasingly recognized in various cardiopulmonary diseases (2528). In this context, studies have shown that, in contrast to the situation in congestive heart failure, the usefulness of surrogate measures of ventilatory efficiency derived from the V.eV.co2 slope is limited as mechanical constraints increase with increasing disease severity in COPD (19, 29). However, these interpretative problems may not apply to mild COPD, in which mechanical derangements are less pronounced.

To date, no study has examined the mechanisms and clinical consequences of a high V.e/V.co2 ratio, measured directly or calculated using the mass balance equation for CO2 [863/PaCO2 × (1 − Vd/Vt)], during exercise in mild COPD. Moreover, the potential interactions between the higher ventilatory demand, abnormal dynamic respiratory mechanics, dyspnea, and exercise tolerance have not been explored in this population. Accordingly, the main objective of the current study was to examine pulmonary gas exchange abnormalities during steady state stages of incremental exercise to tolerance in patients with symptomatic mild COPD and to determine whether the physiological adaptations required to maintain arterial blood gas homeostasis had negative clinical consequences in terms of dynamic respiratory mechanics, increased dyspnea, and exercise intolerance.


Eleven stable patients meeting GOLD grade 1B criteria were included (5). Other inclusion criteria were as follows: age 50 years or older, and a smoking history of at least 10 pack-years. Exclusion criteria were as follows: the presence of asthma; other medical conditions that could contribute to dyspnea or exercise limitation; contraindications to exercise testing; use of daytime oxygen; body mass index less than 18.5 or greater than 35 kg/m2. Eleven age-matched, nonsmoking healthy control subjects were studied for comparison.

Study Design

This cross-sectional study received ethics approval from the Queen’s University and Affiliated Teaching Hospitals Research Ethics Board (DMED-1458-12). After written informed consent was obtained, subjects completed two visits. Visit 1 included screening for eligibility, medical history, and symptom and activity assessment questionnaires (3034); pre- and post-bronchodilator (400 μg salbutamol) pulmonary function tests; tests of small airway function; and an incremental cycle cardiopulmonary exercise test (CPET) for familiarization. Visit 2 included spirometry followed by incremental cycle CPET with detailed measurements of ventilatory, sensory–perceptual, and arterial blood gas responses. Subjects with COPD withdrew short- and long-acting bronchodilators for 6 and 24 hours before visits, respectively. A high-resolution computed tomography (HRCT) scan of the thorax was performed in patients with COPD for quantitative assessment of the extent of emphysema (35).


Detailed pulmonary function tests were performed (Vmax229d and Autobox V62J; MasterScreen impulse oscillometry system [IOS]; SensorMedics, Yorba Linda, CA) (23, 3639). CPET was conducted on an electronically braked cycle ergometer (Ergoline 800s; SensorMedics, Yorba Linda, CA) using a SensorMedics Vmax229d system as previously described (15). Tests consisted of steady state rest followed by 20-W increases in work rate every 3 minutes (i.e., for steady state or near steady state) to symptom limitation. Measurements included standard breath-by-breath cardiorespiratory and breathing pattern parameters, oxygen saturation by pulse oximetry (SpO2), heart rate (HR) by ECG, and dynamic operating lung volumes calculated from inspiratory capacity (IC) maneuvers (15). Expiratory flow limitation (EFL) was evaluated as the percentage of Vt overlapping the maximal expiratory flow–volume loop (15, 17), and dyspnea intensity was assessed with the modified 10-point Borg scale.

An index of ventilatory efficiency was calculated using the mass balance equation for CO2: V.e/V.co2 = 1/PaCO2 × (1 − Vd/Vt). Surrogate markers of ventilatory efficiency included the following: measured V.e/V.co2 ratio at standardized work rates and at its nadir, and the slope and intercept of the V.eV.co2 relationship. As developed by Poon and Tin, the apparent ventilatory equivalent for CO2 was calculated as (V.e/V.co2)/(1 − Vd/Vt) and the apparent metabolic CO2 load was calculated as V.co2/(1 − Vd/Vt) (27, 40). All measurements were taken while breathing ambient air.

Arterial blood samples were withdrawn anaerobically at rest, at every stage of exercise up to 80 W, and at peak exercise, and then analyzed immediately after each test (ABL800 FLEX; Radiometer, Copenhagen, Denmark). Measurements were corrected for body temperature measured by a rapid response wired thermocouple placed in the arterial line (IT-18 with TH5 thermometer; Physitemp, Clifton, NJ). a–aPo2 was estimated using the ideal alveolar gas equation: PaO2 = FiO2(Patm − PH2O) − (PaCO2[1 − FiO2(1 − R)])/R, where FiO2 is the fraction of inspired O2, Patm is atmospheric pressure, PH2O is water vapor pressure at BTPS, and R is the respiratory exchange ratio measured at the time of sampling. Vd/Vt was calculated using the modified Bohr equation: Vd/Vt = [(PaCO2 − PeCO2)/PaCO2] − (Vdm/Vt), where PeCO2 is the partial pressure of mixed expired CO2, and Vdm is the volume of the breathing valve and mouthpiece.

Statistical Analysis

This was an observational physiological study with the main outcome measures consisting of V.e/V.co2, Vd/Vt, and other blood gas measurements during exercise. Because of the complexity and invasiveness of measurements, a planned analysis was undertaken after 11 subjects per group had been tested. In two previous studies incorporating arterial blood gas measurements in patients with COPD at our laboratory (41, 42), this sample size was large enough to detect significant differences in relevant gas exchange variables.

A P < 0.05 level of significance was used for all analyses. Qualitative descriptors of dyspnea and reasons for stopping exercise were compared between groups by Fisher exact test. Unpaired t tests were used to compare group differences in (1) pulmonary function tests and measurements of small airway function; and (2) dyspnea intensity and cardiorespiratory, metabolic, gas exchange, and operating lung volumes at rest and during isowork rates and peak exercise.

Groups were well matched for age, height, mass, and body mass index. Patients had worse activity-related dyspnea, higher COPD Assessment Test scores, and poorer health-related quality of life compared with control subjects (Table 1). None of our patients was treated for angina, previous myocardial infarction, or congestive heart failure. Comorbidities in the COPD group included well-controlled hypercholesterolemia (n = 5), gastroesophageal reflux disease (n = 5), systemic hypertension (n = 4), obstructive sleep apnea (n = 3), chronic sinusitis (n = 3), and diabetes mellitus type 2 (n = 1). Chest HRCT scans revealed 15 ± 11% of the patients’ lungs as low-attenuation areas (less than –950 HU).

Table 1. Subject Characteristics

 Mild COPDHealthy
Male:female, n6:55:6
Age, yr64.0 ± 1164.1 ± 10
Height, cm167 ± 11169 ± 8
Body mass, kg77.1 ± 15.978.9 ± 11.7
BMI, kg/m227.2 ± 3.427.5 ± 3.3
Smoking history, pack-years35.6 ± 14.9*1.5 ± 3.2
Smoking status, % current smokers45%*0%
BDI focal score, 0–128.0 ± 1.2*11.8 ± 0.6
Modified MRC dyspnea scale, 0–42.0 ± 0.4*0.3 ± 0.5
CAT score, 0–4015.6 ± 7.7*2.9 ± 1.9
Oxygen cost diagram (0–100), mm64 ± 11*94 ± 10
SGRQ total score29.6 ± 16.8*2.5 ± 1.6
CHAMPS, kcal/wk for all activities3,901 ± 2,7535,100 ± 3,820
Medication use, % of patients:  
 Combined ICS/LABA45*0

Definition of abbreviations: BDI = modified Baseline Dyspnea Index; BMI = body mass index; CAT = COPD Assessment Test; CHAMPS = Community Healthy Activities Model Program for Seniors questionnaire; COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroid; LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; MRC = Medical Research Council; SABA = short-acting β2-agonist; SGRQ = St. George’s Respiratory Questionnaire.

Values represent means ± SD.

*P < 0.05, patients with mild COPD versus healthy control group.

Pulmonary Function and Small Airway Function

Pulmonary function tests are summarized in Table 2. Patients with COPD had relatively preserved spirometry with no significant response to a bronchodilator (FEV1 improved by 79 ml and 5%). Patients had evidence of small airway dysfunction (e.g., reduction in maximal mid-expiratory flows [FEF25–75%] and increases in the differential change of airway resistance from 5 to 20 Hz [R5–20] and the resonant frequency [Fres] measured by IOS), pulmonary gas trapping (higher residual volume/total lung capacity [RV/TLC]), and ventilatory inhomogeneity (higher closing volume) compared with healthy control subjects. Maximal voluntary ventilation (MVV) was similar in both groups. In COPD, DlCO and Dl/Va (DlCO corrected for alveolar volume) were near normal relative to predicted values but significantly lower compared with control subjects (P < 0.05).

Table 2. Resting Pulmonary Function

 Mild COPDHealthy
Post-bronchodilator pulmonary function
 FEV1, L2.44 ± 0.6* (94 ± 10*)3.01 ± 0.6 (118 ± 15)
 FEV1/FVC, %61 ± 6*74 ± 4
Prebronchodilator pulmonary function
 FEV1, L2.35 ± 0.6* (90 ± 13*)2.96 ± 0.6 (115 ± 16)
 FEV1/FVC, %59.5 ± 5.1* (85 ± 5*)70.0 ± 5.0 (99 ± 9)
 PEF, L/s7.02 ± 1.7* (99 ± 12*)8.29 ± 1.5 (121 ± 8)
 FEF25–75%, L/s0.98 ± 0.4* (37 ± 10*)1.92 ± 0.6 (73 ± 24)
 SVC, L3.99 ± 0.9 (108 ± 14*)4.43 ± 0.8 (123 ± 10)
 IC, L3.00 ± 0.9 (107 ± 26)3.21 ± 0.9 (121 ± 28)
 FRC, L3.16 ± 0.7 (98 ± 16)3.22 ± 0.9 (99 ± 20)
 TLC, L6.16 ± 1.1 (102 ± 11)6.43 ± 1.2 (109 ± 10)
 RV, L2.17 ± 0.5 (99 ± 13)2.00 ± 0.5 (92 ± 19)
 RV/TLC, %35 ± 6*31 ± 4
 DlCO, ml/min/mm Hg16.3 ± 4.8* (78 ± 16*)21.6 ± 4.1 (101 ± 21)
 Dl/Va, ml/min/mm Hg/L3.09 ± 0.6* (82 ± 16*)3.89 ± 0.3 (103 ± 11)
 sRaw, cm H2O·s9.71 ± 2.3* (229 ± 62*)7.16 ± 2.2 (176 ± 60)
 MVV, L/min95.3 ± 29.0116.2 ± 28.3
 Closing volume, L0.74 ± 0.2*0.53 ± 0.2
 N2 slope, %/L5.2 ± 2.34.4 ± 2.1
 R5, cm H2O/L/s5.1 ± 1.64.2 ± 1.7
 R5–20, %R520.0 ± 7.9*13.2 ± 7.7
 X5, cm H2O/L/s−1.2 ± 0.4−1.0 ± 0.4
 Fres, Hz14.5 ± 3.4*10.7 ± 3.2

Definition of abbreviations: COPD = chronic obstructive pulmonary disease; DlCO = diffusing capacity of the lung for carbon monoxide; Dl/Va = DlCO corrected for alveolar volume; FEF25–75% = forced expiratory flow between 25 and 75% of forced vital capacity; FEV1/FVC = ratio between FEV1 and forced vital capacity; Fres = resonant frequency; IC = inspiratory capacity; MVV = maximal voluntary ventilation; PEF = peak expiratory flow; R5 = resistance at 5 Hz during impulse oscillometry; R5–20 = differential change in resistance between 5 and 20 Hz; RV = residual volume; sRaw = specific airway resistance; SVC = slow vital capacity; TLC = total lung capacity; X5 = distal capacitive reactance at 5 Hz.

Values represent means ± SD, with percentage of predicted normal values in parentheses.

*P < 0.05, patients with mild COPD versus healthy control group.

Cardiopulmonary Exercise Test and Gas Exchange Measurements

Arterial blood data are summarized in Table 3 and Figure 1. At rest, arterial blood gases and parameters of acid–base balance were all within normal ranges; however, patients had a lower resting PaO2 and modestly lower oxygen saturation (SaO2) compared with control subjects (Table 3 and Figure 1). The average resting a–aPo2 was significantly higher in patients with mild COPD than in control subjects, and 6 of 11 patients with COPD had values greater than 15 mm Hg. Compared with control subjects, patients with COPD had a significantly higher V.e/V.co2 ratio, dead space ventilation (V.d), dead space volume (Vd), Vd/Vt, and arterial to end-tidal CO2 difference (Pa–etCO2) at rest (all P < 0.05) (Figure 2 and Table 3).

Table 3. Gas Exchange Parameters at Rest, Highest Equivalent Work Rate, and Peak Exercise

VariableRestHEWR (60 W)Peak
Mild COPDHealthyMild COPDHealthyMild COPDHealthy
pH7.43 ± 0.037.41 ± 0.027.40 ± 0.027.39 ± 0.047.38 ± 0.04*7.34 ± 0.03
H+, nmol/L37.5 ± 2.539.1 ± 2.140.0 ± 2.140.3 ± 3.341.9 ± 3.5*45.2 ± 3.2
PaO2, mm Hg94.2 ± 11.2*103.6 ± 8.999.9 ± 13.8108.4 ± 9.7105.4 ± 16.5105.4 ± 10.9
PaCO2, mm Hg34.6 ± 3.836.6 ± 2.934.8 ± 3.437.2 ± 3.330.7 ± 2.929.2 ± 2.8
HCO3, mmol/L22.3 ± 1.722.5 ± 1.221.0 ± 1.9*22.4 ± 1.118.1 ± 2.6*16.0 ± 1.7
SaO2, %97.9 ± 0.6*98.4 ± 0.697.5 ± 1.4*98.7 ± 0.697.7 ± 1.898.0 ± 1.1
Lactate, mmol/L1.0 ± 0.51.1 ± 0.73.1 ± 1.12.3 ± 1.16.6 ± 2.3*9.9 ± 3.1
Vd/Vt0.37 ± 0.08*0.25 ± 0.090.20 ± 0.08*0.11 ± 0.060.15 ± 0.09*0.03 ± 0.07
1/PaCO2 × (1 − Vd/Vt)0.047 ± 0.01*0.037 ± 0.000.037 ± 0.01*0.030 ± 0.000.039 ± 0.000.036 ± 0.00
1/(1 − Vd/Vt)1.6 ± 0.2*1.3 ± 0.21.3 ± 0.1*1.1 ± 0.11.2 ± 0.1*1.0 ± 0.1
V.co2/(1 − Vd/Vt)0.36 ± 0.10.33 ± 0.11.37 ± 0.31.14 ± 0.32.08 ± 0.5*2.58 ± 0.6
Pa–etCO2, mm Hg3.9 ± 2.1*1.4 ± 1.41.6 ± 2.3*−1.0 ± 2.30.95 ± 2.7*−2.4 ± 1.8
a–aPo2, mm Hg18.4 ± 13.9*5.4 ± 6.917.7 ± 15.9*4.9 ± 9.319.4 ± 18.315.1 ± 11.6
V.o2, L/min0.27 ± 0.060.29 ± 0.071.09 ± 0.171.12 ± 0.191.68 ± 0.57*2.34 ± 0.63
V.co2, L/min0.22 ± 0.060.25 ± 0.061.08 ± 0.171.01 ± 0.201.78 ± 0.54*2.50 ± 0.55
V.e, L/min11.8 ± 3.410.2 ± 2.939.4 ± 12.5*30.1 ± 6.867.7 ± 18.685.4 ± 22.8
V.a, L/min7.1 ± 1.97.4 ± 2.530.7 ± 7.126.7 ± 5.555.8 ± 18.3*82.6 ± 22.6
EFL (% of Vt overlap)14 ± 21*0 ± 059 ± 13*28 ± 2072 ± 7*60 ± 10

Definition of abbreviations: 1/(1 − Vd/Vt) and 1/PaCO2 × (1 − Vd/Vt) = indices of ventilatory efficiency; a–aPo2 = alveolar–arterial oxygen tension gradient; COPD = chronic obstructive pulmonary disease; EFL = expiratory flow limitation assessed as percentage of Vt that overlapped the maximal expiratory flow–volume loop; H+ = hydrogen ion concentration; HCO3 = bicarbonate anion concentration; HEWR = highest equivalent work rate performed by all subjects; Pa–etCO2 = arterial-to–end-tidal CO2 gradient; V.a = alveolar ventilation; V.co2 = CO2 production; V.co2/(1 – Vd/Vt) = apparent metabolic CO2 load; Vd/Vt = dead space to tidal volume ratio; V.e = minute ventilation.

Values represent means ± SD.

*P < 0.05, patients with mild COPD versus healthy control group.

Measurements at peak exercise are summarized in Table 4. Patients with COPD had significantly reduced peak work rate and peak V.o2 compared with control subjects. HR responses were higher in patients versus control subjects during exercise, but both groups reached a similar peak (see the online supplement). Increased V.e during exercise in COPD compared with control subjects (Figure 2) was achieved by increased breathing frequency; tidal volume (Vt) responses were similar for a given work rate in both groups up to an inflection/plateau seen late in exercise in COPD (Figure 3). This Vt inflection point occurred at a lower V.e in patients with COPD compared with control subjects: 44.5 ± 13 versus 61.4 ± 16 L/minute, respectively (see the online supplement). Patients with COPD had shorter inspiratory (Ti) and expiratory (Te) times and higher mean inspiratory (Vt/Ti) and expiratory (Vt/Ve) flows at standardized work rates during exercise compared with control subjects (Figure 3). Both groups had a similar IC and inspiratory reserve volume (IRV) at submaximal work rates up to 60 W and reached a similar low IRV at end-exercise; however, at a lower peak work rate in patients with COPD (Figure 3). In addition to having greater dynamic hyperinflation (reduction in IC from rest) during exercise, patients with COPD had significantly greater EFL than control subjects at the highest submaximal work rate achieved by all subjects (60 W) and at peak exercise (Table 3).

Table 4. Measurements at Peak of Symptom-limited Incremental Cycle Exercise

 Mild COPDHealthy
Work rate, W (% predicted)102 ± 43* (68 ± 23*)158 ± 40 (108 ± 25)
V.o2, L/min (% predicted)1.7 ± 0.6* (80 ± 18*)2.3 ± 0.6 (113 ± 24)
V.e, L/min (% MVV)67.7 ± 18.6 (73 ± 13)85.4 ± 22.8 (74 ± 14)
Vt, L1.7 ± 0.5*2.2 ± 0.3
Vt/IC, %65 ± 968 ± 8
Fb, breaths/min41.4 ± 4.938.3 ± 6.9
Ti/Ttot0.47 ± 0.020.48 ± 0.03
IC, L (% predicted)2.7 ± 0.8* (99 ± 21*)3.3 ± 0.4 (124 ± 16)
ΔIC from rest, L−0.16 ± 0.30*0.33 ± 0.4
IRV, L0.9 ± 0.41.0 ± 0.3
EILV, %TLC85 ± 684 ± 5
PetCO2, mm Hg29.8 ± 3.331.5 ± 2.6
V.e/V.co238.6 ± 5.4*33.9 ± 3.0
(V.e/V.co2)/(1 – Vd/Vt)46.3 ± 10.8*35.1 ± 4.5
SpO2, %96.4 ± 2.396.6 ± 1.6
R1.07 ± 0.11.09 ± 0.1
HR, beats/min (% predicted)140 ± 16 (83 ± 9)150 ± 17 (89 ± 10)
O2 pulse, ml/beat11.9 ± 3.5*15.8 ± 4.5
Dyspnea, Borg units6.4 ± 1.45.7 ± 2.6
Leg discomfort, Borg units6.6 ± 2.26.8 ± 3.2
Reason for stopping:  
 Breathing discomfort18%0%
 Leg discomfort0%0%
 Both breathing and leg discomfort82%91%

Definition of abbreviations: COPD = chronic obstructive pulmonary disease; EILV = end-inspiratory lung volume; Fb = breathing frequency; HR = heart rate; IC = inspiratory capacity; IRV = inspiratory reserve volume; MVV = maximal voluntary ventilation; O2 pulse = oxygen pulse; PetCO2 = partial pressure of end-tidal carbon dioxide; R = respiratory exchange ratio; SpO2 = arterial O2 saturation measured by pulse oximetry; Ti/Ttot = inspiratory duty cycle; TLC = total lung capacity; V.e/V.co2 = ventilatory equivalent for carbon dioxide; (V.e/V.co2)/(1 – Vd/Vt) = apparent ventilatory equivalent for CO2.

Values represent means ± SD.

*P < 0.05, patients with mild COPD versus healthy control group.

V.e/V.co2 ratio, V.d, Vd, Vd/Vt, and Pa–etCO2 were higher in patients with COPD than in control subjects throughout exercise (Figure 2). V.eV.co2 relationships expressed as slope, intercept, and nadir were higher in patients with COPD than control subjects: 31.9 ± 5.3 versus 26.3 ± 1.3, 4.5 ± 1.1 versus 3.1 ± 1.2, and 33.6 ± 4.7 versus 26.0 ± 1.1, respectively (all P < 0.05). Accordingly, the partial pressure of end-tidal CO2 (PetCO2) was consistently lower at rest and throughout exercise in patients with COPD compared with control subjects. Patients increased their PaO2 significantly by 11 ± 10 mm Hg (P = 0.005) from rest to peak exercise (Figure 1). PaCO2 and alveolar ventilation (V.a) were similar in both groups throughout exercise; however, PaCO2 tended to be lower in patients than control subjects. SaO2 was lower in patients than control subjects at all submaximal work rates, but there was no significant change from rest-to-peak exercise (Figure 1). a–aPo2 was significantly higher in patients at all submaximal work rates compared with control subjects, but both groups had similar values at peak exercise (Figure 1). Arterial lactate concentration was similar in both groups at rest and at all submaximal work rates; however, healthy control subjects reached significantly higher levels at peak exercise (Table 3). Although the anaerobic threshold was not statistically different between groups, it tended to occur at a lower V.o2 in patients than control subjects: 1.5 and 1.9 L/minute, respectively (P = 0.06). Interestingly, exercise measurements of V.e/V.co2 correlated better with concurrent measurements of Vd/Vt (r = 0.780, P < 0.001) than with PaCO2 (r = 0.452, P < 0.001) in both groups (Figure 4). The index of ventilatory efficiency also correlated better with exercise measurements of Vd/Vt (r = 0.789, P < 0.001) than with PaCO2 (r = 0.631, P < 0.001) (see the online supplement).

Patients with COPD had greater dyspnea intensity ratings at all submaximal work rates compared with control subjects (Figure 5); there was no significant difference between groups in ratings of exertional leg discomfort. Dyspnea intensity ratings relative to V.e expressed as a percentage of MVV were superimposed (Figure 5). Unsatisfied inspiration was a predominant description of dyspnea at peak exercise in patients with COPD (see the online supplement).

The main findings of this study are as follows: (1) physiological dead space and wasted ventilation were greater in patients with mild COPD than in healthy control subjects both at rest and during exercise; (2) our results confirmed that arterial blood gas homeostasis was adequately maintained during incremental exercise in patients as a result of compensatory increases in minute ventilation; and (3) the higher ventilatory demand in the setting of EFL forced earlier mechanical constraints on tidal volume expansion and was associated with earlier onset of severe dyspnea in the mild COPD group. The results indicate that the presence of wasted ventilation in patients with peripheral airway dysfunction can have important clinical consequences, particularly as it relates to dyspnea and physical activity limitation.

In our patients with mild COPD, arterial blood gases at rest were within the normal range, as were indicators of acid–base balance. However, resting PaO2 and O2 saturation were significantly lower than in control subjects. In keeping with previous studies (20, 21), average resting a–aPo2, a measure of venous admixture, was significantly increased compared with control subjects at rest, and 6 of 11 patients with COPD had gradients exceeding 15 mm Hg (21). A more consistent abnormality was that the resting V.e/V.co2 ratio and V.d were significantly elevated compared with control subjects. Collectively, these abnormalities point to the presence of a “dead space effect” due to regional alveolar units being overventilated relative to their blood flow (24). In fact, dead space or wasted ventilation was the dominant gas exchange abnormality and represented almost 40% of total V.e at rest in mild COPD compared with 28% in control subjects. However, despite gas exchange abnormalities in COPD at rest, effective V.a and normal arterial blood gas homeostasis were sustained during incremental exercise when V.o2 increased sixfold.

Consistent with several studies in mild COPD (1519), the V.eV.co2 slope and the V.e/V.co2 nadir were higher in the COPD group than in age-matched control subjects during exercise. The increased V.e/V.co2 ratio was closely associated with established indices of wasted ventilation during exercise such as increased Vd/Vt. It is noteworthy that the higher Vd/Vt ratio did not reflect a lower Vt in patients (Figure 3), that is, Vd per se was higher in patients with COPD than in control subjects. The observation that physiological dead space was higher in patients is in line with a higher Pa–etCO2. In fact, average Pa–etCO2 remained positive during exercise, that is, PetCO2 failed to increase in tandem with the expected increase in pulmonary blood flow. Reduced pulmonary blood perfusion (relative to ventilation) might be expected, for example, with decreased pulmonary capillary density or blood flow and attenuated vessel recruitment and distension as cardiac output increased with exertion (4345). Increase in lung units with high V.a/Q. ratios may be exaggerated in smokers as a result of pulmonary vascular inflammation and remodeling due to direct effects of tobacco smoke as described in patients with mild COPD (12, 43, 45).

In the current study, we could not quantify the relative contribution of altered PaCO2 set point to the increased V.e/V.co2 in COPD (46, 47). However, correlations between the V.e/V.co2 ratio and Vd/Vt were stronger throughout submaximal exercise (i.e., below the anaerobic threshold) than those with PaCO2 (Figure 4). We did not examine potential long-term adaptations of the respiratory controller, which are known to affect V.e/V.co2. However, there was no evidence of chronic compensated respiratory alkalosis in our patients with mild COPD (Table 3). Clinically significant arterial O2 desaturation was not observed during exercise in patients but, as previously shown (20, 21), a–aPo2 was higher compared with control subjects during submaximal exercise. The increased gradient at lower exercise intensities before the ventilatory threshold reflected the relatively reduced PaO2 in mild COPD. However, at higher exercise intensities the increased gradient was mainly due to the relatively increased V.a. Barbera and colleagues (20) provided evidence that the increase in PaO2 during exercise in mild to moderate COPD was the result of increased and more efficient distribution of ventilation rather than improved hemodynamic responses. Our finding that Vd/Vt declined during exercise to a similar extent in both groups also supports the idea that overall V.a/Q. adaptations to the stress of increased metabolic loading were not compromised to a greater extent in our COPD group compared with control subjects. Breathing pattern showed greater breathing frequency in patients with COPD than in control subjects, with significantly shorter Ti and Te and correspondingly higher mean inspiratory and expiratory flows (Figure 3). The greater reliance on increasing breathing frequency (rather than increasing Vt) to increase V.e in response to intrinsic dead space loading in COPD may represent an integrative response of the respiratory system’s central controller to reduce elastic loading of the respiratory muscles, facilitate CO2 elimination, and minimize respiratory discomfort (48).

Although peripheral airway obstruction was undoubtedly present in our patients, dynamic ventilatory constraints became evident only at higher exercise intensities. Thus, mild dynamic hyperinflation (by 0.16 L from rest to end-exercise) occurred as a result of the combination of the higher ventilatory requirements (due to higher physiological dead space) and increased EFL, which constrained normal Vt expansion at higher exercise intensities. It follows that patients reached a Vt inflection/plateau and a similar minimal IRV (≤1 L below TLC) to control subjects but at a significantly lower work rate and V.e (Figure 3; and see the online supplement). Remarkably, despite these dynamic respiratory mechanical constraints and the adoption of a more rapid breathing pattern, the net ventilatory compensatory response to combined effects of intrinsic dead space loading and metabolic acidosis was adequate to ensure normal CO2 elimination even at the peak of exercise.

The relatively greater V.e in COPD was not without negative consequences: dyspnea ratings were higher in association with greater V.e/MVV, a measure of the ventilatory demand–capacity imbalance. Thus, at a standardized work rate (60 W), dyspnea ratings were significantly higher, by close to 2 Borg units in COPD, reflecting a concomitantly (18%) higher V.e/MVV (Figure 5). This finding is in line with an article on mild COPD that shows a close relationship between dyspnea intensity and increased respiratory neural drive (relative to maximum) during exercise, as indirectly measured by electromyography of the diaphragm (13). However, the higher dyspnea ratings in mild COPD are unlikely to be due to the higher ventilation per se. In this context, previous studies have shown that the addition of an extrinsic dead space (0.6 L) to the breathing circuit of healthy older control subjects during exercise consistently stimulated ventilation (by increasing Vt) but did not increase dyspnea (14, 49). By contrast, added dead space of similar magnitude in patients with mild COPD, who had a limited ability to expand Vt, significantly amplified dyspnea intensity (14). It follows that the increased respiratory neural drive, reflecting increasing V.co2 from combined metabolic and pulmonary compartments (apparent V.co2) (27), forced earlier critical mechanical constraints on increasing ventilation in the setting of increased EFL in COPD. Thus, it is the interaction between the increased drive and the constrained mechanical response that explains the greater dyspnea in patients with COPD. The more frequent selection of the qualitative descriptor “unsatisfied inspiration” at end-exercise in the mild COPD group than in control subjects is consistent with this hypothesis as previously described (50).


The study sample was necessarily small given the invasive nature of the testing but was sufficiently large to uncover significant physiological differences in the parameters of interest between the groups. Given the heterogeneous nature of the physiological impairment in mild COPD and variability in the degree of chronic dyspnea, our sample may not be representative of the larger population. Nevertheless, the study was sufficiently powered to investigate the origins of increased V.e/V.co2 in symptomatic mild COPD, a consistent abnormality in all of the exercise studies conducted to date in this population (1519). The current study did not evaluate potential adaptations to pulmonary gas exchange impairment by the cardiocirculatory system, the peripheral muscles (O2 delivery/use), or the autonomic nervous system.


This study is the first to show increased wasted ventilation in smokers with only minor spirometric abnormalities. Compensatory increases in V.e maintained effective V.a and arterial blood gas homeostasis during exercise but at the expense of forcing earlier dynamic respiratory mechanical constraints and greater respiratory discomfort. Thus, the results of this study uncovered an important source of exertional dyspnea in mild COPD (increased ventilatory inefficiency and demand) that is not widely appreciated and not necessarily amenable to bronchodilator therapy. The study provides a physiological rationale for clinical exercise testing, which includes simple surrogate measures of ventilatory efficiency such as the V.e/V.co2 ratio and V.eV.co2 slope for smokers who present with chronic activity–related dyspnea that appears disproportionate to their minor spirometric abnormality. Finally, our results set the stage for novel mechanistic studies of V.a/Q. inequalities in mild COPD, with particular reference to the nature and extent of pulmonary perfusion abnormalities which could potentially be targeted for treatment.

1. Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC. Chronic obstructive pulmonary disease surveillance—United States, 1971–2000. MMWR Surveill Summ 2002;51:116.
2. Buist AS, McBurnie MA, Vollmer WM, Gillespie S, Burney P, Mannino DM, Menezes AM, Sullivan SD, Lee TA, Weiss KB, et al.; BOLD Collaborative Research Group. International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. Lancet 2007;370:741750.
3. Hashimoto N, Matsuzaki A, Okada Y, Imai N, Iwano S, Wakai K, Imaizumi K, Yokoi K, Hasegawa Y. Clinical impact of prevalence and severity of COPD on the decision-making process for therapeutic management of lung cancer patients. BMC Pulm Med 2014;14:14.
4. Bridevaux PO, Gerbase MW, Probst-Hensch NM, Schindler C, Gaspoz JM, Rochat T. Long-term decline in lung function, utilisation of care and quality of life in modified GOLD stage 1 COPD. Thorax 2008;63:768774.
5. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease [updated 2014 Jan 23; accessed 2014 Nov]. Available from:
6. Mannino DM, Buist AS, Petty TL, Enright PL, Redd SC. Lung function and mortality in the United States: data from the First National Health and Nutrition Examination Survey follow up study. Thorax 2003;58:388393.
7. Antonelli-Incalzi R, Imperiale C, Bellia V, Catalano F, Scichilone N, Pistelli R, Rengo F; SaRA Investigators. Do GOLD stages of COPD severity really correspond to differences in health status? Eur Respir J 2003;22:444449.
8. Ferrer M, Alonso J, Morera J, Marrades RM, Khalaf A, Aguar MC, Plaza V, Prieto L, Antó JM; Quality of Life of Chronic Obstructive Pulmonary Disease Study Group. Chronic obstructive pulmonary disease stage and health-related quality of life. Ann Intern Med 1997;127:10721079.
9. Watz H, Waschki B, Boehme C, Claussen M, Meyer T, Magnussen H. Extrapulmonary effects of chronic obstructive pulmonary disease on physical activity: a cross-sectional study. Am J Respir Crit Care Med 2008;177:743751.
10. Pitta F, Troosters T, Spruit MA, Probst VS, Decramer M, Gosselink R. Characteristics of physical activities in daily life in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;171:972977.
11. Boland MRS, Tsiachristas A, Kruis AL, Chavannes NH, Rutten-van Mölken MP. Are GOLD ABCD groups better associated with health status and costs than GOLD 1234 grades? A cross-sectional study. Prim Care Respir J 2014;23:3037.
12. Barbera JA, Ramirez J, Roca J, Wagner PD, Sanchez-Lloret J, Rodriguez-Roisin R. Lung structure and gas exchange in mild chronic obstructive pulmonary disease. Am Rev Respir Dis 1990;141:895901.
13. Guenette JA, Chin RC, Cheng S, Dominelli PB, Raghavan N, Webb KA, Neder JA, O’Donnell DE. Mechanisms of exercise intolerance in global initiative for chronic obstructive lung disease grade 1 COPD. Eur Respir J 2014;44:11771187.
14. Chin RC, Guenette JA, Cheng S, Raghavan N, Amornputtisathaporn N, Cortés-Télles A, Webb KA, O’Donnell DE. Does the respiratory system limit exercise in mild chronic obstructive pulmonary disease? Am J Respir Crit Care Med 2013;187:13151323.
15. Ofir D, Laveneziana P, Webb KA, Lam YM, O’Donnell DE. Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage I chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177:622629.
16. Guenette JA, Jensen D, Webb KA, Ofir D, Raghavan N, O’Donnell DE. Sex differences in exertional dyspnea in patients with mild COPD: physiological mechanisms. Respir Physiol Neurobiol 2011;177:218227.
17. Elbehairy A, Raghavan N, Cheng S, Yang L, Webb KA, Neder JA, Guenette JA, Mahmoud MI, O’Donnell DE; Canadian Respiratory Research Network. Physiological characterization of the chronic bronchitis phenotype in GOLD grade 1B COPD. Chest [online ahead of print] 13 Nov 2014; DOI: 10.1378/chest.14-1491.
18. O’Donnell DE, Maltais F, Porszasz J, Webb KA, Albers FC, Deng Q, Iqbal A, Paden HA, Casaburi R; 205.440 investigators. The continuum of physiological impairment during treadmill walking in patients with mild-to-moderate COPD: patient characterization phase of a randomized clinical trial. PLoS One 2014;9:e96574.
19. Neder JA, Arbex FF, Alencar MC, O’Donnell CD, Cory J, Webb KA, O’Donnell DE. Exercise ventilatory inefficiency in mild to end-stage COPD. Eur Respir J 2015;45:377387.
20. Barbera JA, Roca J, Ramirez J, Wagner PD, Ussetti P, Rodriguez-Roisin R. Gas exchange during exercise in mild chronic obstructive pulmonary disease: correlation with lung structure. Am Rev Respir Dis 1991;144:520525.
21. Rodríguez-Roisin R, Drakulovic M, Rodríguez DA, Roca J, Barberà JA, Wagner PD. Ventilation–perfusion imbalance and chronic obstructive pulmonary disease staging severity. J Appl Physiol2009;106:19021908.
22. Corbin RP, Loveland M, Martin RR, Macklem PT. A four-year follow-up study of lung mechanics in smokers. Am Rev Respir Dis 1979;120:293304.
23. Buist AS. Early detection of airways obstruction by the closing volume technique. Chest 1973;64:495499.
24. Wasserman K, Hansen JE, Sue DY, Whipp BJ, Casaburi R. Principles of exercise testing and interpretation, 3rd ed. Baltimore: Lippincott Williams & Wilkins; 1999.
25. Teopompi E, Tzani P, Aiello M, Gioia MR, Marangio E, Chetta A. Excess ventilation and ventilatory constraints during exercise in patients with chronic obstructive pulmonary disease. Respir Physiol Neurobiol 2014;197:914.
26. Teopompi E, Tzani P, Aiello M, Ramponi S, Visca D, Gioia MR, Marangio E, Serra W, Chetta A. Ventilatory response to carbon dioxide output in subjects with congestive heart failure and in patients with COPD with comparable exercise capacity. Respir Care 2014;59:10341041.
27. Poon CS, Tin C. Mechanism of augmented exercise hyperpnea in chronic heart failure and dead space loading. Respir Physiol Neurobiol 2013;186:114130.
28. Reybrouck T, Mertens L, Schulze-Neick I, Austenat I, Eyskens B, Dumoulin M, Gewillig M. Ventilatory inefficiency for carbon dioxide during exercise in patients with pulmonary hypertension. Clin Physiol 1998;18:337344.
29. Thirapatarapong W, Armstrong HF, Thomashow BM, Bartels MN. Differences in gas exchange between severities of chronic obstructive pulmonary disease. Respir Physiol Neurobiol 2013;186:8186.
30. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J 2009;34:648654.
31. Fletcher CM, Elmes PC, Fairbairn AS, Wood CH. The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. BMJ 1959;2:257266.
32. Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea: contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest 1984;85:751758.
33. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation: the St. George’s Respiratory Questionnaire. Am Rev Respir Dis 1992;145:13211327.
34. McGavin CR, Artvinli M, Naoe H, McHardy GJ. Dyspnoea, disability, and distance walked: comparison of estimates of exercise performance in respiratory disease. BMJ 1978;2:241243.
35. Coxson HO, Rogers RM, Whittall KP, D’yachkova Y, Paré PD, Sciurba FC, Hogg JC. A quantification of the lung surface area in emphysema using computed tomography. Am J Respir Crit Care Med 1999;159:851856.
36. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CPM, Gustafsson P, et al.; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J 2005;26:319338.
37. Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, Casaburi R, Crapo R, Enright P, van der Grinten CPM, et al.; ATS/ERS Task Force on Standardisation of Lung Function Testing. Standardisation of the measurement of lung volumes. Eur Respir J 2005;26:511522.
38. Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CPM, Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, et al.; ATS/ERS Task Force on Standardisation of Lung Function Testing. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J 2005;26:720735.
39. Oostveen E, MacLeod D, Lorino H, Farré R, Hantos Z, Desager K, Marchal F; ERS Task Force on Respiratory Impedance Measurements. The forced oscillation technique in clinical practice: methodology, recommendations and future developments. Eur Respir J 2003;22:10261041.
40. Ward SA. Commentary on “Mechanism of augmented exercise hyperpnea in chronic heart failure and dead space loading” by Poon and Tin. Respir Physiol Neurobiol 2013;189:203210.
41. O’Donnell DE, Bain DJ, Webb KA. Factors contributing to relief of exertional breathlessness during hyperoxia in chronic airflow limitation. Am J Respir Crit Care Med 1997;155:530535.
42. O’Donnell DE, D’Arsigny C, Webb KA. Effects of hyperoxia on ventilatory limitation during exercise in advanced chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:892898.
43. Wright JL, Lawson L, Paré PD, Hooper RO, Peretz DI, Nelems JM, Schulzer M, Hogg JC. The structure and function of the pulmonary vasculature in mild chronic obstructive pulmonary disease: the effect of oxygen and exercise. Am Rev Respir Dis 1983;128:702707.
44. Janssens JP, Pache JC, Nicod LP. Physiological changes in respiratory function associated with ageing. Eur Respir J 1999;13:197205.
45. Santos S, Peinado VI, Ramírez J, Melgosa T, Roca J, Rodriguez-Roisin R, Barberà JA. Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD. Eur Respir J 2002;19:632638.
46. Whipp BJ. Ventilatory control during exercise in humans. Annu Rev Physiol 1983;45:393413.
47. Ward SA, Whipp BJ. Ventilatory control during exercise with increased external dead space. J Appl Physiol 1980;48:225231.
48. Poon CS. Potentiation of exercise ventilatory response by airway CO2 and dead space loading. J Appl Physiol 1992;73:591595.
49. Faisal A, Webb KA, Guenette JA, Jensen D, Neder JA, O’Donnell DE; Canadian Respiratory Research Network. Effect of age-related ventilatory inefficiency on respiratory sensation during exercise. Respir Physiol Neurobiol 2015;205:129139.
50. Laveneziana P, Webb KA, Ora J, Wadell K, O’Donnell DE. Evolution of dyspnea during exercise in chronic obstructive pulmonary disease: impact of critical volume constraints. Am J Respir Crit Care Med 2011;184:13671373.
Correspondence and requests for reprints should be addressed to Denis E. O’Donnell, M.D., 102 Stuart Street, Kingston, ON, K7L 2V6 Canada. E-mail:

Supported by the Ontario Thoracic Society; William Spear/Richard Start Endowment Fund, Queen’s University; and the Canadian Respiratory Research Network (CRRN). The CRRN is supported by grants from the Canadian Institutes of Health Research (CIHR)–Institute of Circulatory and Respiratory Health; Canadian Lung Association (CLA)/Canadian Thoracic Society (CTS); British Columbia Lung Association; and Industry Partners Boehringer-Ingelheim Canada Ltd., AstraZeneca Canada Inc., and Novartis Canada Ltd. Financial support to A.F.E. was provided by an Egyptian Ministry of Higher Education and Scientific Research Scholarship. J.A.G. was supported by a Scholar Award from the Michael Smith Foundation for Health Research. D.J. was supported by a Chercheurs-Boursiers Junior 1 salary award from the Fonds de Recherche du Québec-Santé and by a William Dawson Research Scholar Award. The funders had no role in the study design, data collection and analysis, or preparation of the manuscript.

Author Contributions: All authors played a role in the content and writing of the manuscript. In addition: D.E.O’D. was the principal investigator and contributed the original idea for the study; D.E.O’D., A.F.E., and K.A.W. had input into the study design and conduct of study; A.F.E. and C.E.C. collected the data; and A.F.E. performed data analysis and prepared it for presentation.

This article has an online supplement, which is accessible from this issue’s table of contents online at

Originally Published in Press as DOI: 10.1164/rccm.201501-0157OC on March 13, 2015

Author disclosures are available with the text of this article at

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